Stem cell therapies hold great promise for treatment of human disease, particularly for currently incurable neurodegenerative diseases. However, to effectively harness the healing potential of stem cells, it is necessary to understand how these cells interact with and respond to their environment. In transplants, stem cells may function as replacement cells that respond to local cues to help mend damaged tissue. They may also function as a source of protective cues, secreting in their undifferentiated state growth factors that facilitate local repair processes. This proposal focuses on this second, less well understood role of stem cells as neuromodulatory secretory cells. The goal of this proposal is to investigate the regulatory and neuroprotective role of adult neural stem/progenitor cell (NPC)-derived secretions in the hippocampus. Given the prominent degradation of the hippocampus in several neurodegenerative disorders such as temporal lobe epilepsy and Alzheimer's disease, this brain area provides an attractive target for stem cell therapy. The Wyss-Coray lab has previously shown that isolated adult hippocampal NPCs secrete a variety of growth factors in large quantities, most notably the highly neuroprotective vascular endothelial growth factor (VEGF). My goal is to investigate the hypothesis that NPC- derived VEGF regulates hippocampal function and provides neuroprotection from degenerative disease. In Aim 1, I will determine how NPC-derived VEGF regulates the proliferation and differentiation of other NPCs in vitro and in vivo using genetic knockdown techniques specific to NPCs. In Aim 2, I will use the in vivo knockdown models from Aim 1 to determine how NPC- derived VEGF regulates the local vascular environment and hippocampal behavior in adult mice. Finally, in Aim 3, I will test the neuroprotective qualities of NPC-derived VEGF from endogenous NPCs (and from NPC transplants) in an excitotoxic model of neural insult. These studies will help provide critical understanding of how NPCs may function as future therapies in vivo. This project combines basic neuroscience with translational research, requiring that I become proficient in a broad skill set. I will gain experience in in vitro NPC culture, shRNA, lox- cre genetics, stereotaxic injectios into the hippocampus and neurodegenerative models of disease. Through this project, it is my goal to acquire expertise in translational research designed to pursue treatment for neurodegenerative disease.